Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation.
We previously documented that a stringent implementation of a preemptive cytomegalovirus (CMV) prevention protocol reduced the number of CMV disease episodes after kidney transplantation, when compared with a routine preemptive protocol. The impact on overall costs was assessed. Cost comparisons were made for inpatient and outpatient costs and overall costs, using costs provided by the financial department. Variables were analyzed using the Wilcoxon rank-sum test. A multivariable global linear model evaluated the effect of all co-variables on cost differences. In Cohort 1 (n = 84), 74% were followed with a standard CMV preemptive protocol, and 26% received prophylaxis. In Cohort 2 (n = 74), an intensified CMV surveillance protocol was applied in 74% of patients, and 26% were given prophylaxis. Overall, Cohort 1 had significantly higher treatment costs as compared with Cohort 2 (mean Swiss francs [CHF] 104,548 and CHF 76,983, respectively, P = 0.0005). Excluding patients who received prophylaxis reduced these costs to CHF 89,318 in Cohort 1 and CHF 73,652 in Cohort 2. Outcome between Cohort 1 and 2 was comparable. A stringent adherence to the CMV prevention protocol was associated with a significant reduction in overall costs. Whether this benefit is because of the demonstrated reduction in the rate of CMV disease needs to be assessed in a randomized trial.


Do liberal blood transfusions cause more harm than good?
Guidelines and evidence from randomised controlled trials and meta-analyses increasingly support restrictive blood transfusion, but it is being implemented only slowly, explain Lawrence Tim Goodnough: and Michael Murphy: . They argue that electronic systems for clinical decision support could improve blood use.


Safety and efficacy of aneurysm treatment with WEB: results of the WEBCAST study.
OBJECT WEB is an innovative intrasaccular treatment for intracranial aneurysms. Preliminary series have shown good safety and efficacy. The WEB Clinical Assessment of Intrasaccular Aneurysm Therapy (WEBCAST) trial is a prospective European trial evaluating the safety and efficacy of WEB in wide-neck bifurcation aneurysms. METHODS Patients with wide-neck bifurcation aneurysms for which WEB treatment was indicated were included in this multicentergood clinical practices study. Clinical data including adverse events and clinical status at 1 and 6 months were collected and independently analyzed by a medical monitor. Six-month follow-up digital subtraction angiography was also performed and independently analyzed by a core laboratory. Success was defined at 6 months as complete occlusion or stable neck remnant, no worsening in angiographic appearance from postprocedure, and no retreatment performed or planned. RESULTS Ten European neurointerventional centers enrolled 51 patients with 51 aneurysms. Treatment with WEB was achieved in 48 of 51 aneurysms (94.1%). Adjunctive implants (coils/stents) were used in 4 of 48 aneurysms (8.3%). Thromboembolic events were observed in 9 of 51 patients (17.6%), resulting in a permanent deficit (modified Rankin Scale [mRS] Score 1) in 1 patient (2.0%). Intraoperative rupture was not observed. Morbidity (mRS score > 2) and mortality were 2.0% (1 of 51 patients, related to rupture status on entry to study) and 0.0% at 1 month, respectively. Success was achieved at 6 months in 85.4% of patients treated with WEB: 23 of 41 patients (56.1%) had complete occlusion, 12 of 41 (29.3%) had a neck remnant, and 6 of 41 (14.6%) had an aneurysm remnant. CONCLUSIONS The WEBCAST study showed good procedural and short-term safety of aneurysm treatment with WEB and good 6-month anatomical results.


Assessing the impacts of livestock production on biodiversity in rangeland ecosystems.
Biodiversity in rangelands is decreasing, due to intense utilization for livestock production and conversion of rangeland into cropland; yet the outlook of rangeland biodiversity has not been considered in view of future global demand for food. Here we assess the impact of future livestock production on the global rangelands area and their biodiversity. First we formalized existing knowledge about livestock grazing impacts on biodiversity, expressed in mean species abundance (MSA) of the original rangeland native species assemblages, through metaanalysis of peer-reviewed literature. MSA values, ranging from 1 in natural rangelands to 0.3 in man-made grasslands, were entered in the IMAGE-GLOBIO model. This model was used to assess the impact of change in food demand and livestock production on future rangeland biodiversity. The model revealed remarkable regional variation in impact on rangeland area and MSA between two agricultural production scenarios. The area of used rangelands slightly increases globally between 2000 and 2050 in the baseline scenario and reduces under a scenario of enhanced uptake of resource-efficient production technologies increasing production [high levels of agricultural knowledge, science, and technology (high-AKST)], particularly in Africa. Both scenarios suggest a global decrease in MSA for rangelands until 2050. The contribution of livestock grazing to MSA loss is, however, expected to diminish after 2030, in particular in Africa under the high-AKST scenario. Policies fostering agricultural intensification can reduce the overall pressure on rangeland biodiversity, but additional measures, addressing factors such as climate change and infrastructural development, are necessary to totally halt biodiversity loss.


LSD1 engages a corepressor complex for the activation of the estrogen receptor α by estrogen and cAMP.
The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of the transcriptional coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors and identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen. Surprisingly, ERα engages not only LSD1, but its partners of the CoREST corepressor complex and the molecular chaperone Hsp90. The recruitment of Hsp90 to promote ERα transcriptional activity runs against the steroid receptor paradigm and suggests that it might be involved as an assembly factor or scaffold. In a breast cancer cell line, which is resistant to the anti-estrogen tamoxifen because of constitutively activated PKA, some interactions are constitutive and drug combinations partially rescue tamoxifen sensitivity. In ERα-positive breast cancer patients, high expression of the genes encoding some of these factors correlates with poor prognosis. Thus, these mechanisms might contribute to ERα-driven breast cancer.


Knots: attractive places with high path tortuosity in mouse open field exploration.
When introduced into a novel environment, mammals establish in it a preferred place marked by the highest number of visits and highest cumulative time spent in it. Examination of exploratory behavior in reference to this "home base" highlights important features of its organization. It might therefore be fruitful to search for other types of marked places in mouse exploratory behavior and examine their influence on overall behavior.Examination of path curvatures of mice exploring a large empty arena revealed the presence of circumscribed locales marked by the performance of tortuous paths full of twists and turns. We term these places knots, and the behavior performed in them-knot-scribbling. There is typically no more than one knot per session; it has distinct boundaries and it is maintained both within and across sessions. Knots are mostly situated in the place of introduction into the arena, here away from walls. Knots are not characterized by the features of a home base, except for a high speed during inbound and a low speed during outbound paths. The establishment of knots is enhanced by injecting the mouse with saline and placing it in an exposed portion of the arena, suggesting that stress and the arousal associated with it consolidate a long-term contingency between a particular locale and knot-scribbling.In an environment devoid of proximal cues mice mark a locale associated with arousal by twisting and turning in it. This creates a self-generated, often centrally located landmark. The tortuosity of the path traced during the behavior implies almost concurrent multiple views of the environment. Knot-scribbling could therefore function as a way to obtain an overview of the entire environment, allowing re-calibration of the mouse's locale map and compass directions. The rich vestibular input generated by scribbling could improve the interpretation of the visual scene.


[A Swiss multicentric project to improve the prevention of cardiovascular event recurrence after acute coronary syndromes].
Recurrence of cardiovascular events and mortality remain high after acute coronary syndromes. A Swiss multicentric study, "Inflammation and acute coronary syndromes (ACS)--Novel strategies for prevention and clinical managements", is currently underway with the support of the Swiss National Science Foundation. The study includes a clinical research subproject of which the aim is to assess the impact of the ELIPS program (multi-dimEnsionaL prevention Program after acute coronary Syndrome) on the recurrence of cardiovascular events after an ACS. The basic research sub-projects aim to investigate novel cardiovascular risk biomarkers and genetic determinants of recurrence and to study the role of stem cells after an ACS. Another sub-project will evaluate intracoronary imaging techniques and the efficacy of different types of stents.


Behavioral and prefrontal representation of spatial proportions in the monkey.
Primate brains are equipped with evolutionarily old and dedicated neural circuits so that they can grasp absolute quantities, such as the number of items or the length of a line. Absolute magnitude, however, is often not informative enough to guide decisions in conflicting social and foraging situations that require an assessment of quantity ratios. We report that rhesus monkeys can discriminate proportions (1:4, 2:4, 3:4, and 4:4) specified by bars differing in lengths and that they can do so at a precision comparable to that shown by humans; the monkeys thus demonstrate an abstract understanding of proportionality. Moreover, neurons in the lateral prefrontal cortex selectively responded to preferred proportions regardless of the exact physical appearance of the stimuli. These results support the hypothesis that nonhuman primates can judge proportions and utilize the underlying information in behaviorally relevant situations.


Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis.
Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.


Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.
Melanoma is the most serious, highly aggressive form of skin cancer with recent dramatic increases in incidence. Current therapies are relatively ineffective, highlighting the need for a better understanding of the molecular mechanisms contributing to the disease. We have previously shown that activation of Rap1 promotes melanoma cell proliferation and migration through the mitogen-activated protein kinase pathway and integrin activation. In the present study, we show that expression of Rap1GAP, a specific negative regulator of Rap1, is decreased in human melanoma tumors and cell lines. Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. In addition, overexpression of Rap1GAP also inhibits focal adhesion formation and decreases melanoma cell migration. Rap1GAP down-regulation is due to its promoter methylation, a mechanism of gene silencing in tumors. Furthermore, treatment of melanoma cells with the demethylating agent 5-aza-2'-deoxycytidine reinduces Rap1GAP expression, followed by decreased Rap1 activity, ERK phosphorylation, and cell proliferation and survival-changes that are significantly blunted in cells transfected by small interfering RNA-mediated Rap1GAP knockdown. Taken together, our findings indicate that down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.


Shared decision-making in dementia care planning: barriers and facilitators in two European countries.
Shared decision-making (SDM) is a means of allowing people with dementia to take part in making choices, be autonomous and participate in social activities. Involving them in SDM is an important way of promoting social health. However, including families and dementia residents in decision-making can be challenging for care staff working in nursing homes. The objective of this study was to identify barriers and facilitators regarding the implementation of an SDM framework for care planning in two nursing homes, one in Italy and one in the Netherlands. Focus group interviews were conducted with healthcare professionals who, after being trained, applied the SDM framework. Content analysis was used to analyze the data. Six months after the feasibility trial, focus group interviews with healthcare professionals (n = 10 in Italy; n = 9 in the Netherlands) were held. We found 6 themes and 15 categories. Within these themes, facilitators and barriers were identified. The categories of team collaboration, communication skills and nursing home policy were found to be facilitators to the implementation process, whereas regulations, lack of funding and of involvement of family caregivers were the main barriers. Family attitudes towards SDM could be both. The main difference between countries concerned the residents' cognitive status that influenced their degree of involvement. Communication skills training for professionals, training of family caregivers, and involvement of the management in the implementation process seem to be crucial factors in successfully implementing SDM in nursing homes, and increasing the involvement of families and dementia residents in decision-making.


When visual transients impair tactile change detection: a novel case of crossmodal change blindness?
The inability of people to detect changes between consecutively presented visual displays, when separated by a blank screen or distractor, is known as "change blindness". This phenomenon has recently been reported to occur within the auditory and tactile modalities as well. To date, however, only distractors presented within the same sensory modality as the change have been demonstrated to produce change blindness. In the present experiment, we studied whether tactile change blindness might also be elicited by the presentation of a visual mask. Participants made same versus different judgments regarding two successively presented displays composed of two to three vibrotactile stimuli. While change detection performance was near-perfect when the two displays were presented one directly after the other, participants failed to detect many of the changes between the tactile displays when they were separated by an empty temporal interval. Critically, performance deteriorated still further when the presentation of a local (i.e., a mudsplash) or global visual transient coincided with the onset of the second tactile pattern. Analysis of the results using signal detection theory revealed that this crossmodal effect reflected a genuine perceptual impairment.


[Remifentanil versus dexmedetomidine as coadjutants of standardized anesthetic technique in morbidly obese patients.].
Two coadjuvant anesthetic drugs - remifentanil and dexmedetomidine - were compared in terms of anesthetic recovery, arterial pH and PaCO2 evolution, in morbidly obese patients submitted to Capella's surgery. Participated in this prospective, randomized and double blind study 92 patients divided in two groups and submitted to standardized anesthetic technique (general/epidural). Remifentanil Group (Group R) and Dexmedetomidine Group (Group D) received continuous intravenous infusion of these drugs (0.1 microg.kg-1.min-1 and 0.5 microg.kg-1.h-1, ideal body weight plus 30% for both) immediately after tracheal intubation. Monitoring consisted of invasive mean blood pressure, pulse oximetry, BIS EEG, capnography, peripheral nerve stimulator and EKG. The following parameters were evaluated: 1) different anesthetic recovery times (eye opening, return to spontaneous ventilation, tracheal extubation time, time for post anesthetic recovery unit and hospital discharge); 2) arterial blood gas analysis evolution; and 3) postoperative analgesia. Evaluation was possible in 88 patients. Patients group R had earlier eye opening (9.49 +/- 5.61 min versus 18.25 +/- 10.24 min, p < 0.0001), faster return to spontaneous ventilation (9.78 +/- 5.80 min versus 16.58 +/- 6.07 min, p < 0.0001), and earlier tracheal extubation (17.93 +/- 10.39 min versus 27.53 +/- 13.39 min, p < 0.0001). There were no differences in times for post-anesthetic recovery unit (105.18 +/- 50.82 min versus 118.69 +/- 56.18 min) and hospital (51.13 +/- 6.37 hours versus 52.50 +/- 7.09 hours) discharge. Both groups showed arterial pH and PaO2 decrease immediately after tracheal extubation as compared to preoperative values, still present at PACU discharge. Group D patients showed higher arterial PaCO2 after tracheal extubation, as compared to preoperative values in the same group (p < 0.05), and opposed to Group R. 41% of Group R and 60% Group D patients (p < 0.02) required rescue analgesia during the first postoperative day. In the studied population, the association of remifentanil to standardized anesthetic technique has resulted in faster anesthetic recovery, stability of preoperative arterial PaCO2 values during the immediate postoperative period and lower postoperative rescue analgesics consumption, as compared to dexmedetomidine.


Exploration of machine learning techniques in predicting multiple sclerosis disease course.
To explore the value of machine learning methods for predicting multiple sclerosis disease course. 1693 CLIMB study patients were classified as increased EDSS≥1.5 (worsening) or not (non-worsening) at up to five years after baseline visit. Support vector machines (SVM) were used to build the classifier, and compared to logistic regression (LR) using demographic, clinical and MRI data obtained at years one and two to predict EDSS at five years follow-up. Baseline data alone provided little predictive value. Clinical observation for one year improved overall SVM sensitivity to 62% and specificity to 65% in predicting worsening cases. The addition of one year MRI data improved sensitivity to 71% and specificity to 68%. Use of non-uniform misclassification costs in the SVM model, weighting towards increased sensitivity, improved predictions (up to 86%). Sensitivity, specificity, and overall accuracy improved minimally with additional follow-up data. Predictions improved within specific groups defined by baseline EDSS. LR performed more poorly than SVM in most cases. Race, family history of MS, and brain parenchymal fraction, ranked highly as predictors of the non-worsening group. Brain T2 lesion volume ranked highly as predictive of the worsening group. SVM incorporating short-term clinical and brain MRI data, class imbalance corrective measures, and classification costs may be a promising means to predict MS disease course, and for selection of patients suitable for more aggressive treatment regimens.


Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis.
Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.


Occurrence, oral exposure and risk assessment of volatile organic compounds in drinking water for Izmir.
Concentrations of volatile organic compounds (VOCs) were measured in the drinking water in Province of Izmir, Turkey, and associated health risks due to ingestion of these compounds were investigated using population weighted random samples. A total of 100 houses were visited in different districts of Izmir and drinking water samples were collected from consumers' drinking water source. Questionnaires were administered to one participant in each house to determine demographics and drinking water consumption rates. Oral exposure and risks were estimated for each participant and Izmir population by deterministic and probabilistic approaches, respectively. The four trihalomethane (THM) species (i.e., chloroform, bromodichloromethane, dibromochloromethane, and bromoform), benzene, toluene, p-xylene, and naphthalene were the most frequently detected VOCs with concentrations ranging from below detection limit to 35 microg/l. The risk estimates were found to be less than the values reported in the literature with few exceptions. Noncarcinogenic risks attributable to ingestion of VOCs for Izmir population were negligible, whereas the mean carcinogenic risk estimates for bromodichloromethane and dibromochloromethane were above the de minimis level of one in a million (10(-6)). For all VOCs, the concentrations measured in metropolitan area were greater than those in other districts. All THM species were detected in higher concentrations in tap water, whereas nontap water contained more benzene, toluene, p-xylene, and naphthalene. Therefore, the concentrations of the latter four compounds and associated risks increased with increasing income and education level since bottled water was used in larger proportions within these subgroups. The results of this study showed that oral exposure to drinking water contaminants and associated risks may be higher than the acceptable levels even if the concentrations fall below the standards.


Lensless imaging from diffraction intensity measurements by use of a noniterative phase-retrieval method.
A method of reconstructing the complex amplitude of an object that is illuminated by a coherent wave from its Fresnel diffraction patterns is proposed for high-frequency wave phenomena such as x-rays and electron waves. A noniterative phase-retrieval method that uses a Gaussian filter is employed here, and it is shown that the object's illumination with amplitude distribution in the Fraunhofer diffraction pattern of a circular aperture can be used as a substitute for the Gaussian filter. This method has an advantage over other noniterative phase-retrieval methods in that it can retrieve phase vortices.


p16INK4A immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia.
In situ hybridization (ISH) assays for high-risk human papillomavirus (HR-HPV) and immunohistochemical (IHC) assays for surrogate markers such as p16 can be useful in detecting HR-HPV in cervical dysplasia, but the use of these markers in problematic cervical biopsies has not been well-established. We evaluated 3 chromogenic ISH assays (Ventana INFORM HPVII and HPVIII and DakoCytomation GenPoint) in conjunction with p16 IHC and HPV polymerase chain reaction in a study set consisting of 12 low-grade squamous intraepithelial lesions, 16 high-grade squamous intraepithelial lesions, and 30 benign cervix samples. A test set of 28 cases of atypical squamous metaplasia were also evaluated withVentana HPVIII ISH and p16 IHC. In the study set, the sensitivity of the DakoCytomation ISH assay (which detects HPV subtypes 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, and 68) was similar to the Ventana HPVII assay but less than that of the Ventana HPVIII ISH assay (both of which detect HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) and less than p16 IHC (55.6% vs. 53.6 vs. 69.2% vs. 82.1%). All HPV ISH assays exhibited 100% specificity. p16 reactivity consisted of 2 patterns: focal strong and diffuse strong. Because focal strong p16 reactivity was identified in benign squamous epithelium (6.7% cases) and dysplastic epithelium, it was considered an equivocal result and only diffuse strong reactivity was considered to be specific for the presence of HR-HPV. In the squamous intraepithelial lesions study set, the difference in sensitivity between Ventana HPVIII ISH and p16 was not statistically significant. However, in the atypical squamous metaplasia test set cases, p16 reactivity (focal strong and diffuse strong) was significantly more sensitive than Ventana HPVIII ISH in correlating with the presence of human papillomavirus as detected by polymerase chain reaction (83.3% vs. 33.3% P=0.004). Because focal strong p16 reactivity is less specific, cases with this staining pattern are considered atypical and require further evaluation by other means. Overall, p16 IHC is considered the best candidate for the initial assessment of cervical biopsies that are histologically indeterminate for dysplasia given its wide availability, comparative ease of interpretation, and high sensitivity and specificity.


Autologous blood injection to treat achilles tendinopathy? A randomized controlled trial.
Achilles tendinopathy is a common and often debilitating condition, and autologous blood injection is a promising treatment option. To determine whether autologous blood injection added to standard management was effective in alleviating symptoms of Achilles tendinopathy. A prospective randomized controlled trial. Private sports medicine clinic. 33 patients (18 women, 15 men) of mean age 50 y (SD 9) with 40 cases of Achilles tendinopathy of mean duration of 11 mo (SD 7). Participants were randomized to blind peritendinous autologous blood injection added to standard treatment (eccentric-loading exercises) or standard treatment alone for 12 wk. Victorian Institute of Sport Assessment for Achilles (VISA-A) score and ratings of discomfort during and after the injection were measured at baseline and 6 and 12 wk. Analytically derived effect-size thresholds of 5 (small) and 15 (moderate) VISA-A units were used as the reference values for clinical inference. Improvements in VISA-A of 7.7 units (95%CL: ± 6.7) and 8.7 units (± 8.8) were observed in the treatment and control groups, respectively, at 6 wk relative to baseline, with no clear effect of blood injection. At 12 wk VISA-A score improved to 18.9 units (± 7.4) in the treatment group, revealing a blood-injection effect of 9.6 units (± 11.5), relative to a comparatively unchanged condition in control (9.4 units; ± 9.0). Predictors of response to treatment were unremarkable, and a 21% rate of postinjection flare was the only noteworthy side effect. There is some evidence for small short-term symptomatic improvements with the addition of autologous blood injection to standard treatment for Achilles tendinopathy, although double-blinded studies with longer follow-up and larger sample size are required.


Differentially expressed genes linked to natural variation in long-term memory formation in Cotesia parasitic wasps.
Even though learning and memory are universal traits in the Animal Kingdom, closely related species reveal substantial variation in learning rate and memory dynamics. To determine the genetic background of this natural variation, we studied two congeneric parasitic wasp species, Cotesia glomerata and C. rubecula, which lay their eggs in caterpillars of the large and small cabbage white butterfly. A successful egg laying event serves as an unconditioned stimulus (US) in a classical conditioning paradigm, where plant odors become associated with the encounter of a suitable host caterpillar. Depending on the host species, the number of conditioning trials and the parasitic wasp species, three different types of transcription-dependent long-term memory (LTM) and one type of transcription-independent, anesthesia-resistant memory (ARM) can be distinguished. To identify transcripts underlying these differences in memory formation, we isolated mRNA from parasitic wasp heads at three different time points between induction and consolidation of each of the four memory types, and for each sample three biological replicates, where after strand-specific paired-end 100 bp deep sequencing. Transcriptomes were assembled de novo and differential expression was determined for each memory type and time point after conditioning, compared to unconditioned wasps. Most differentially expressed (DE) genes and antisense transcripts were only DE in one of the LTM types. Among the DE genes that were DE in two or more LTM types, were many protein kinases and phosphatases, small GTPases, receptors and ion channels. Some genes were DE in opposing directions between any of the LTM memory types and ARM, suggesting that ARM in Cotesia requires the transcription of genes inhibiting LTM or vice versa. We discuss our findings in the context of neuronal functioning, including RNA splicing and transport, epigenetic regulation, neurotransmitter/peptide synthesis and antisense transcription. In conclusion, these brain transcriptomes provide candidate genes that may be involved in the observed natural variation in LTM in closely related Cotesia parasitic wasp species.


Preference for Cocaine is Represented in the Orbitofrontal Cortex by an Increased Proportion of Cocaine Use-Coding Neurons.
Cocaine addiction is a harmful preference for drug use over and at the expense of other nondrug-related activities. Here we identify in the rat orbitofrontal cortex (OFC) a mechanism that explains individual preferences between cocaine use and an alternative, nondrug action. OFC neuronal activity was recorded while rats performed each of these 2 actions separately or while they chose between them. First, we found that these actions are encoded by 2 nonoverlapping neuronal populations and that the relative size of the cocaine population represented individual preferences. A larger relative size was only observed in cocaine-preferring individuals. Second, OFC neurons encoding a given individual's preferred action progressively fired more than other action-coding neurons few seconds before the preferred action was actually chosen, suggesting a prechoice neuronal competition for action selection. In cocaine-preferring rats, this manifested by a prechoice ramping-up activity in favor of the cocaine population. Finally, pharmacological manipulation of prechoice activity in favor of the cocaine population caused nondrug-preferring rats to shift their choice to cocaine. Overall, this study suggests that an individual preference for cocaine is represented in the OFC by a population size bias that systematically advantages cocaine use-coding neurons during prechoice competition for action selection.


Filopodia: the fingers that do the walking.
Filopodia are actin-based structures composed of parallel bundles of actin filaments and various actin-associated proteins, and they play important roles in cell-cell signaling, guidance toward chemoattractants, and adhesion to the extracellular matrix. Two mechanisms for the formation of filopodia have been suggested, each using different sets of actin-regulating proteins, creating some controversy in the field. New molecules, some of unknown functions, have also been implicated in filopodium formation, suggesting that other possible mechanisms of filopodium formation exist. We discuss established and novel proteins that mediate the formation and dynamics of filopodia, different mechanisms of filopodium formation, and the various functions that distinct filopodia perform.


Synthesis and studies on the effect of 2-thiouridine and 4-thiouridine on sugar conformation and RNA duplex stability.
In order to understand the effect of 2-thiouridine (s2U) substitution on RNA structure and the potential for stabilization of tRNA codon-anticodon interactions through s2U-34 modification, a pentamer RNA sequence, Gs2UUUC, was synthesized and characterized by NMR spectroscopy. The single strand contains the UUU anticodon sequence of tRNALys with flanking GCs to increase duplex stability. Regiochemical effects of uridine thiolation were determined by comparing the structure and stability of the 2-thiouridine containing oligonucleotide with an identical sequence containing 4-thiouridine (s4U) and also the normal uridine nucleoside. Circular dichroism spectrum indicated an A-form helical conformation for Gs2UUUC which was further confirmed by 2D ROESY NMR experiments. The duplex stability of the three pentamers complexed with a 2'-O-methyl-ribonucleotide complementary strand, GmAmAmAmCm, was determined by UV thermal melting studies and by 1H NMR spectroscopy. The duplex containing s2U has a T m of 30.7 degrees C compared to 19. 0 degrees C for the unmodified control and 14.5 degrees C for the s4U containing duplex. The results from UV experiments were corroborated by imino proton NMR studies that show proton exchange rates, chemical shift differences, and NH proton linewidths indicative of the stability order s2U >U >s4U. The magnitude of the effect of s2U in our model system is comparable to the 20 degrees C stabilization observed by Grosjean and co-workers for 2-thiolation in a codon-anticodon model system composed of two tRNAs with complementary anticodon sequences [Houssier, C., Degee, P., Nicoghosian, K. and Grosjean, H. (1988) J. Biomol. Struct. Dyn., 5, 1259-1266].


Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.
This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.


Whole-genome sequencing revealed concurrent outbreaks of shigellosis in the English Orthodox Jewish Community caused by multiple importations of Shigella sonnei from Israel.
In December 2013, Public Health England (PHE) observed an increase in the number of cases of Shigella sonnei linked to the Orthodox Jewish Community (OJC). Ultimately, 52 cases of S. sonnei phage type (PT) P and PT7 were notified between November 2013 and July 2014. Whole-genome sequencing (WGS) was performed on a HiSeq 2500 platform (Illumina) on isolates of S. sonnei submitted to PHE during the investigation. Quality trimmed sequence reads were mapped to a reference genome using BWA-MEM, and single-nucleotide polymorphisms (SNPs) were identified using GATK2. Analysis of the core genome SNP positions (>90 % consensus, minimum depth 10×, MQ≥30) revealed that isolates linked to the outbreak could be categorized as members of distinct monophyletic clusters (MPCs) representing concurrent regional outbreaks occurring in the OJCs across the United Kingdom. A dated phylogeny predicted the date of the most recent common ancestor of the MPCs to be approximately 3.1 years previously [95 % highest posterior density (HPD), 2.4-3.4]. Isolates of S. sonnei from cases from the OJCs in Israel included in the phylogeny, branched from nodes basal to the UK OJC outbreak clusters, indicating they were ancestral to the UK OJC isolates, and that the UK isolates represented multiple importations of S. sonnei into the UK population from Israel. The level of discrimination exhibited by WGS facilitated the identification of clusters of isolates within the closely related bacterial populations circulating in the OJC that may be linked to a unique point sources or transmission routes, thus enabling a more appropriate public health response and targeted interventions.


Recovery outcomes of schizophrenia patients treated with paliperidone palmitate in a community setting: patient and provider perspectives on recovery.
This study evaluated the effect of paliperidone palmitate long-acting injectable (LAI) antipsychotic on recovery-oriented mental health outcomes from the perspective of healthcare providers and patients during the treatment of patients with schizophrenia or schizoaffective disorders. Archival data for patients with a primary diagnosis of schizophrenia or schizoaffective disorder receiving ≥6 months of paliperidone palmitate LAI were retrieved from the electronic medical records system at the Mental Health Center of Denver. Mental health recovery was assessed from both a provider's (Recovery Markers Inventory [RMI]) and patient's (Consumer Recovery Measure [CRM]) perspective. A three-level hierarchical linear model (HLM) was utilized to determine changes in CRM and RMI scores by including independent variables in the models: intercept, months from treatment (slope), treatment time period (pretreatment and treatment), age, gender, primary diagnosis, substance abuse diagnosis, concurrent medications, and adherence to paliperidone palmitate LAI. A total of 219 patients were identified and included in the study. Results of the final three-level HLMs indicated an overall increase in CRM scores (p < 0.05), an overall increase (p < 0.01), and an increased rate of change (p < 0.05) in RMI scores during the paliperidone palmitate LAI treatment period vs the pre-treatment period. This study contained a retrospective, non-comparative design, and did not adjust for multiplicity Conclusions: The current study demonstrates that changes in recovery-oriented mental health outcomes can be detected following the administration of a specific antipsychotic treatment in persons with schizophrenia or schizoaffective disorders. Furthermore, patients receiving paliperidone palmitate LAI can effectively improve recovery-oriented outcomes, thereby supporting the drug's use as schizophrenia treatment from a recovery-oriented perspective.


Using passive sampling and zebrafish to identify developmental toxicants in complex mixtures.
Using effects-directed analysis, we investigated associations previously observed between polycyclic aromatic hydrocarbons (PAHs) and embryotoxicity in field-deployed low-density polyethylene (LDPE). We conducted effects-directed analysis using a zebrafish embryo assay and iterative fractionation of extracts of LDPE that were deployed in the Portland Harbor superfund megasite, Oregon (USA). Whole extracts induced toxicity including mortality, edema, and notochord distortion at 20% effect concentration (EC20) values of approximately 100, 100, and 10 mg LDPE/mL, respectively. Through fractionation, we determined that PAHs at concentrations similar to previous research did not contribute markedly to toxicity. We also eliminated pesticides, phthalates, musks, and other substances identified in toxic fractions by testing surrogate mixtures. We identified free fatty acids as lethal components of LDPE extracts and confirmed their toxicity with authentic standards. We found chromatographic evidence that dithiocarbamates are responsible for notochord and other sublethal effects, although exact matches were not obtained. Fatty acids and dithiocarbamates were previously unrecorded components of LDPE extracts and likely contribute to the toxicity of the whole mixture. The present study demonstrates the success of effects-directed analysis in nontargeted hazard identification using the zebrafish embryo test as a self-contained battery of bioassays that allows identification of multiple chemicals with different modes of action. This is the first effects-directed analysis to combine LDPE and zebrafish, approaches that are widely applicable to identifying developmental hazards in the bioavailable fraction of hydrophobic organic compounds. Environ Toxicol Chem 2017;36:2290-2298. © 2017 SETAC.


Covering one eye affects how some children read.
The Dunlop Test was used to identify unstable binocular control in a group of 32 mixed-ability children. They were compared with 32 reading age-matched controls. The children were then asked to read two lists of single real words of equal linguistic difficulty: one with both eyes open and the other with the left eye occluded. Only children who failed the Dunlop Test made fewer non-word errors when they read with one eye. This result provides additional support for the theory that unstable binocular control can directly affect how children read. In addition, these findings suggest that this effect must be due, at least in part, to some interaction between the images from the two eyes.


A conceptual framework for patient-directed knowledge tools to support patient-centred care: Results from an evidence-informed consensus meeting.
Patient-directed knowledge tools are designed to engage patients in dialogue or deliberation, to support patient decision-making or self-care of chronic conditions. However, an abundance of these exists. The tools themselves and their purposes are not always clearly defined; creating challenges for developers and users (professionals, patients). The study's aim was to develop a conceptual framework of patient-directed knowledge tool types. A face-to-face evidence-informed consensus meeting with 15 international experts. After the meeting, the framework went through two rounds of feedback before informal consensus was reached. A conceptual framework containing five patient-directed knowledge tool types was developed. The first part of the framework describes the tools' purposes and the second focuses on the tools' core elements. The framework provides clarity on which types of patient-directed tools exist, the purposes they serve, and which core elements they prototypically include. It is a working framework and will require further refinement as the area develops, alongside validation with a broader group of stakeholders. The framework assists developers and users to know which type a tool belongs, its purpose and core elements, helping them to develop and use the right tool for the right job.


An expert consensus framework for asthma remission as a treatment goal.
With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.


High-intensity Interval training enhances mobilization/functionality of endothelial progenitor cells and depressed shedding of vascular endothelial cells undergoing hypoxia.
Exercise training improves endothelium-dependent vasodilation, whereas hypoxic stress causes vascular endothelial dysfunction. Monocyte-derived endothelial progenitor cells (Mon-EPCs) contribute to vascular repair process by differentiating into endothelial cells. This study investigates how high-intensity interval (HIT) and moderate-intensity continuous (MCT) exercise training affect circulating Mon-EPC levels and EPC functionality under hypoxic condition. Sixty healthy sedentary males were randomized to engage in either HIT (3-min intervals at 40 and 80 % VO2max for five repetitions, n = 20) or MCT (sustained 60 % VO2max, n = 20) for 30 min/day, 5 days/week for 6 weeks, or to a control group (CTL) that did not received exercise intervention (n = 20). Mon-EPC characteristics and EPC functionality under hypoxic exercise (HE, 100 W under 12 % O2) were determined before and after HIT, MCT, and CTL. The results demonstrated that after the intervention, the HIT group exhibited larger improvements in VO2peak, estimated peak cardiac output (QC), and estimated peak perfusions of frontal cerebral lobe (QFC) and vastus lateralis (QVL) than the MCT group. Furthermore, HIT (a) increased circulating CD14++/CD16-/CD34+/KDR+ (Mon-1 EPC) and CD14++/CD16+/CD34+/KDR+ (Mon-2 EPC) cell counts, (b) promoted the migration and tube formation of EPCs, (c) diminished the shedding of endothelial (CD34-/KDR+/phosphatidylserine+) cells, and (d) elevated plasma nitrite plus nitrate, stromal cell-derived factor-1, matrix metalloproteinase-9, and vascular endothelial growth factor-A concentrations at rest or following HE, compared to those of MCT. In addition, Mon-1 and -2 EPC counts were directly related to VO2peak and estimated peak QC, QFC, and QVL. HIT is superior to MCT for improving hemodynamic adaptation and Mon-EPC production. Moreover, HIT effectively enhances EPC functionality and suppresses endothelial injury undergoing hypoxia.


Choice of Antiviral Allocation Scheme for Pandemic Influenza Depends on Strain Transmissibility, Delivery Delay and Stockpile Size.
Recently, pandemic response has involved the use of antivirals. These antivirals are often allocated to households dynamically throughout the pandemic with the aim being to retard the spread of infection. A drawback of this is that there is a delay until infection is confirmed and antivirals are delivered. Here an alternative allocation scheme is considered, where antivirals are instead preallocated to households at the start of a pandemic, thus reducing this delay. To compare these two schemes, a deterministic approximation to a novel stochastic household model is derived, which allows efficient computation of key quantities such as the expected epidemic final size, expected early growth rate, expected peak size and expected peak time of the epidemic. It is found that the theoretical best choice of allocation scheme depends on strain transmissibility, the delay in delivering antivirals under a dynamic allocation scheme and the stockpile size. A broad summary is that for realistic stockpile sizes, a dynamic allocation scheme is superior with the important exception of the epidemic final size under a severe pandemic scenario. Our results, viewed in conjunction with the practical considerations of implementing a preallocation scheme, support a focus on attempting to reduce the delay in delivering antivirals under a dynamic allocation scheme during a future pandemic.


Endodontic Procedural Errors by Students in Two Saudi Dental Schools.
To explore endodontic procedural errors committed by undergraduate dental students in King Khalid University (KKU), Abha and AlFarabi dental college, Riyadh. In this cross sectional study, a questionnaire was distributed to 500 dental students from both schools and of both genders in the 5th and 6th levels in the academic year 2016-2017. Participants were asked to record their endodontic procedural error(s) that had occurred during training. Returned and eligible questionnaires were 469 (93.8% response rate) and were almost equally distributed by university (KKU and Alfarabi). The participants' age ranged from 22 to 24 years, and approximately 47% of them were female students and 65% were 6th level students. Almost 56% of the sample reported at least one endodontic procedural error during their training. Female students reported errors (65%) more frequently than the male students (49%; P=0.002). Up to 54% of these errors were in the posterior teeth and 65% were in teeth with curved roots. Most common error during access cavity preparation was gouging (68%) and due to instrumentation was ledge formation (47%), during obturation was voids (41%). There were no differences in the reported endodontic errors between the two universities. The frequency of reported endodontic procedural errors by senior dental students in both schools, more specifically those in the 6th year, is high. Ledge formation and voids in the root canal filling are the most frequently reported endodontic errors.


Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats.
The continuous search for a novel neuropathic pain drug with few or no side effects has been a main focus of researchers for decades. This study investigated the antinociceptive and neuroprotective effects of bromelain in sciatic nerve ligation-induced neuropathic pain in Wistar rats. Forty-eight Wistar rats randomly divided into eight groups comprised of six animals each were used for this study. Peripheral neuropathy was induced via chronic constriction of the common sciatic nerve. Thermal hyperalgesic and mechanical allodynia were assessed using a hotplate and von Frey filaments, respectively. The functional recovery and structural architecture of the ligated sciatic nerve were evaluated using the sciatic functional index test and a histological examination of the transverse section of the sciatic nerve. The neuroprotective effects of bromelain were investigated in the proximal sciatic nerve tissue after 21 days of treatment. Bromelain significantly (P < 0.05) attenuated both the thermal hyperalgesia and mechanical allodynic indices of neuropathic pain. There were improvements in sciatic function and structural integrity in rats treated with bromelain. These rats showed significant (P < 0.05) increases in sciatic nerve nuclear transcription factors (nuclear factor erythroid-derived-2-related factors-1 [NrF-1] and NrF-2), antioxidant enzymes (superoxide dismutase and glutathione), and reduced membrane-lipid peroxidation compared with the ligated control group. This study suggest that bromelain mitigated neuropathic pain by enhancing the activities of nuclear transcription factors (NrF-1 and NrF-2) which increases the antioxidant defense system that abolish neuronal stress and structural disorganization.


Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia.
Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.


Crystal structure of the Sema-PSI extracellular domain of human RON receptor tyrosine kinase.
Human RON (Recepteur d'Origine Nantais) receptor tyrosine kinase is a cell surface receptor for Macrophage Stimulating Protein (MSP). RON mediates signal transduction pathways that regulate cell adhesion, invasion, motility and apoptosis processes. Elevated levels of RON and its alternatively spliced variants are implicated in the progression and metastasis of tumor cells. The binding of MSP α/β heterodimer to the extracellular region of RON receptor induces receptor dimerization and activation by autophosphorylation of the intracellular kinase domains. The ectodomain of RON, containing the ligand recognition and dimerization domains, is composed of a semaphorin (Sema), Plexins-Semaphorins-Integrins domain (PSI), and four Immunoglobulins-Plexins-Transcription factor (IPT) domains. High affinity association between MSP and RON is mediated by the interaction between MSP β-chain and RON Sema, although RON activation requires intact RON and MSP proteins. Here, we report the structure of RON Sema-PSI domains at 1.85 Å resolution. RON Sema domain adopts a seven-bladed β-propeller fold, followed by disulfide bond rich, cysteine-knot PSI motif. Comparison with the homologous Met receptor tyrosine kinase reveals that RON Sema-PSI contains distinguishing secondary structural features. These define the receptors' exclusive selectivity towards their respective ligands, RON for MSP and Met for HGF. The RON Sema-PSI crystal packing generates a homodimer with interface formed by the Sema domain. Mapping of the dimer interface using the RON homology to Met, MSP homology to Hepatocyte Growth Factor (HGF), and the structure of the Met/HGF complex shows the dimer interface overlapping with the putative MSPβ binding site. The crystallographically determined RON Sema-PSI homodimer may represent the dimer assembly that occurs during ligand-independent receptor activation and/or the inhibition of the constitutive activity of RONΔ160 splice variant by the soluble RON splice variant, RONΔ85.


Percutaneous right ventricle outflow tract stenting in a patient with trisomy 18 associated with double outlet right ventricle.
Trisomy 18, or Edwards syndrome, is the second most common chromosome anomaly after trisomy 21. Various types of congenital heart diseases are seen in the majority of trisomy 18 patients. Palliative treatment of right ventricular outflow tract (RVOT) stenosis includes options like balloon dilatation, stenting and surgery. Herein, we present a case with trisomy 18 and double outlet right ventricle, pulmonary stenosis, and ventricular septal defect. During the follow-up, at the age of three months, his saturation dropped to 70% and an interventional procedure was planned. The patient was considered high risk, and after discussing treatment options with the family, RVOT stenting was chosen. The patient was lost on the 8th day of the follow-up.


Prevalence and correlates of depressive symptoms among high school students in Hanover, Jamaica.
The objective of this study was to determine the prevalence of depressive symptoms in Jamaican adolescents and examine its association with individual and family factors. We used an abbreviated form of the Beck's Depression Inventory II (BDI-II) to assess depressive symptoms among 748 students, attending public high schools in the parish of Hanover Jamaica. In the analysis, we classified adolescents with scores in the upper quartile of the depressive symptom score as having depressive symptoms. Multivariate logistic regression was used to determine the predictors of depressive symptoms. 14.2% of participants reported depressive symptoms. There was association between engagement in sexual activity [Odds Ratio (OR) = 1.61, 95% Confidence Interval (CI) = 1.02-2.51], parental monitoring of adolescent activity (OR=2.04, 95%CI=1.33 -3.12), maternal affection and support (OR= 4.07, 95%CI= 2.62-6.33), and paternal affection and support (OR= 1.58, 95%CI= 1.05-2.39) with self reported depressive symptoms at the bivariate level. In the final model, depressive symptoms was associated with perceived lack of maternal affection and support (OR= 4.06, 95%CI= 2.61-6.32) and showed marginal association with being sexually experienced (OR= 1.59, 95%CI= 1.00-2.52). As most homes are female-headed, establishing support systems for the mother to take care of their adolescent children may decrease the odds of depressive symptoms. Sexually experienced adolescents may require screening for depression. Further research is required to fully explore all factors that could predispose Jamaican adolescents to depression.


A systematic review of changing malaria disease burden in sub-Saharan Africa since 2000: comparing model predictions and empirical observations.
The most widely used measures of declining burden of malaria across sub-Saharan Africa are predictions from geospatial models. These models apply spatiotemporal autocorrelations and covariates to parasite prevalence data and then use a function of parasite prevalence to predict clinical malaria incidence. We attempted to assess whether trends in malaria cases, based on local surveillance, were similar to those captured by Malaria Atlas Project (MAP) incidence surfaces. We undertook a systematic review (PROSPERO International Prospective Register of Systematic Reviews; ID = CRD42019116834) to identify empirical data on clinical malaria in Africa since 2000, where reports covered at least 5 continuous years. The trends in empirical data were then compared with the trends of time-space matched clinical malaria incidence from MAP using the Spearman rank correlation. The correlations (rho) between changes in empirically observed and modelled estimates of clinical malaria were displayed by forest plots and examined by meta-regression. Sixty-seven articles met our inclusion criteria representing 124 sites from 24 African countries. The single most important factor explaining the correlation between empirical observations and modelled predictions was the slope of empirically observed data over time (rho = - 0.989; 95% CI - 0.998, - 0.939; p < 0.001), i.e. steeper declines were associated with a stronger correlation between empirical observations and modelled predictions. Factors such as quality of study, reported measure of malaria and endemicity were only slightly predictive of such correlations. In many locations, both local surveillance data and modelled estimates showed declines in malaria burden and hence similar trends. However, there was a weak association between individual surveillance datasets and the modelled predictions where stalling in progress or resurgence of malaria burden was empirically observed. Surveillance data were patchy, indicating a need for improved surveillance to strengthen both empiric reporting and modelled predictions.


TREVO and Capture LP have equal technical success rates in mechanical thrombectomy of proximal and distal anterior circulation occlusions.
Mechanical thrombectomy (MT) is a proven method to treat large vessel occlusions in acute anterior circulation stroke. We compared the technical, imaging, and clinical outcomes of MT performed with either TREVO or Capture LP devices. There were 42 and 43 patients in the TREVO and Capture LP groups, respectively. Baseline variables, technical outcome (Thrombolysis In Cerebral Infarction, TICI), 24 hours imaging outcome, and 3-month clinical outcome (modified Rankin Scale, mRS) were prospectively recorded. The patients were stratified according to clot location, groups compared, and logistic regression models devised to study the effect of device selection on the clinical outcome. The technical success rates were equal in both proximal (internal carotid artery and proximal M1 segment) and distal occlusions (distal M1 and M2 segments). The proportion of TICI 2b or 3 was 96% and 87% with TREVO and 87% and 89% with Capture LP (p=0.25 and p=0.80, respectively). Device selection did not significantly predict good clinical outcome (mRS ≤2) in either proximal or distal occlusions. In multivariate analysis, selecting Capture LP borderline significantly increased the odds of an excellent outcome close to sixfold both in proximal and distal occlusions (OR 6.7, 95% CI 0.82 to 53.7, p=0.08 and OR 5.7, 95% CI 0.88 to 37.8, p=0.07, respectively). TREVO and Capture LP perform equally well in proximal and distal occlusions in the anterior circulation when technical and good clinical outcome are considered. Capture LP may have a small advantage in reaching mRS ≤1 at 3 months. However, this needs to be confirmed in a randomized study.


Anticancer activity of subfractions containing pure compounds of Chaga mushroom (Inonotus obliquus) extract in human cancer cells and in Balbc/c mice bearing Sarcoma-180 cells.
The Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat cancers. However, limited information exists on the underlying anticancer effects of the major component of I. obliquusin vivo. We hypothesize that the pure compounds (3beta-hydroxy-lanosta-8,24-dien-21-al, inotodiol and lanosterol, respectively) separated from I. obliquus would inhibit tumor growth in Balbc/c mice bearing Sarcoma-180 cells (S-180) in vivo and growth of human carcinoma cells in vitro. To test this hypothesis, the growth inhibition of each subfraction isolated from I. obliquus on human carcinoma cell lines (lung carcinoma A-549 cells, stomach adenocarcinoma AGS cells, breast adenocarcinoma MCF-7 cells, and cervical adenocarcinoma HeLa cells) was tested in vitro. Then, after S-180 implantation, the mice were fed a normal chow supplemented with 0, 0.1 or 0.2 mg of subfraction 1, 2 or 3 per mouse per day. All of the subfractions isolated from I. obliquus showed significant cytotoxic activity against the selected cancer cell lines in vitro. Subfraction 1 was more active than subfraction 2 and subfraction 3 against the A549, AGS and MCF-7 cancer cell lines in vitro. In in vivo results, subfraction 1 isolated from I. obliquus at concentrations of 0.1 and 0.2 mg/mouse per day significantly decreased tumor volume by 23.96% and 33.71%, respectively, as compared with the control. Subfractions 2 and 3 also significantly inhibited tumor growth in mice bearing S-180 as compared with the control mouse tumor. Subfraction 1 isolated from I. obliquus showed greater inhibition of tumor growth than subfractions 2 and 3, which agrees well with the in vitro results. The results suggest that I. obliquus and its compounds in these subfractions isolated from I. obliquus could be used as natural anticancer ingredients in the food and/or pharmaceutical industry.


How Consistent is the Relationship between Improved Glucose Control and Modelled Health Outcomes for People with Type 2 Diabetes Mellitus? a Systematic Review.
There are an increasing number of studies using simulation models to conduct cost-effectiveness analyses for type 2 diabetes mellitus. To evaluate the relationship between improvements in glycosylated haemoglobin (HbA1c) and simulated health outcomes in type 2 diabetes cost-effectiveness studies. A systematic review was conducted on MEDLINE and EMBASE to collect cost-effectiveness studies using type 2 diabetes simulation models that reported modelled health outcomes of blood glucose-related interventions in terms of quality-adjusted life-years (QALYs) or life expectancy (LE). The data extracted included information used to characterise the study cohort, the intervention's treatment effects on risk factors and model outcomes. Linear regressions were used to test the relationship between the difference in HbA1c (∆HbA1c) and incremental QALYs (∆QALYs) or LE (∆LE) of intervention and control groups. The ratio between the ∆QALYs and ∆LE was calculated and a scatterplot between the ratio and ∆HbA1c was used to explore the relationship between these two. Seventy-six studies were included in this research, contributing to 124 pair of comparators. The pooled regressions indicated that the marginal effect of a 1% HbA1c decrease in intervention resulted in an increase in life-time QALYs and LE of 0.371 (95% confidence interval 0.286-0.456) and 0.642 (95% CI 0.494-0.790), respectively. No evidence of heterogeneity between models was found. An inverse exponential relationship was found and fitted between the ratio (∆QALY/∆LE) and ∆HbA1c. There is a consistent relationship between ∆HbA1c and ∆QALYs or ∆LE in cost-effectiveness analyses using type 2 diabetes simulation models. This relationship can be used as a diagnostic tool for decision makers.


Increased Callosal Connectivity in Reeler Mice Revealed by Brain-Wide Input Mapping of VIP Neurons in Barrel Cortex.
The neocortex is composed of layers. Whether layers constitute an essential framework for the formation of functional circuits is not well understood. We investigated the brain-wide input connectivity of vasoactive intestinal polypeptide (VIP) expressing neurons in the reeler mouse. This mutant is characterized by a migration deficit of cortical neurons so that no layers are formed. Still, neurons retain their properties and reeler mice show little cognitive impairment. We focused on VIP neurons because they are known to receive strong long-range inputs and have a typical laminar bias toward upper layers. In reeler, these neurons are more dispersed across the cortex. We mapped the brain-wide inputs of VIP neurons in barrel cortex of wild-type and reeler mice with rabies virus tracing. Innervation by subcortical inputs was not altered in reeler, in contrast to the cortical circuitry. Numbers of long-range ipsilateral cortical inputs were reduced in reeler, while contralateral inputs were strongly increased. Reeler mice had more callosal projection neurons. Hence, the corpus callosum was larger in reeler as shown by structural imaging. We argue that, in the absence of cortical layers, circuits with subcortical structures are maintained but cortical neurons establish a different network that largely preserves cognitive functions.


City size and the spreading of COVID-19 in Brazil.
The current outbreak of the coronavirus disease 2019 (COVID-19) is an unprecedented example of how fast an infectious disease can spread around the globe (especially in urban areas) and the enormous impact it causes on public health and socio-economic activities. Despite the recent surge of investigations about different aspects of the COVID-19 pandemic, we still know little about the effects of city size on the propagation of this disease in urban areas. Here we investigate how the number of cases and deaths by COVID-19 scale with the population of Brazilian cities. Our results indicate small towns are proportionally more affected by COVID-19 during the initial spread of the disease, such that the cumulative numbers of cases and deaths per capita initially decrease with population size. However, during the long-term course of the pandemic, this urban advantage vanishes and large cities start to exhibit higher incidence of cases and deaths, such that every 1% rise in population is associated with a 0.14% increase in the number of fatalities per capita after about four months since the first two daily deaths. We argue that these patterns may be related to the existence of proportionally more health infrastructure in the largest cities and a lower proportion of older adults in large urban areas. We also find the initial growth rate of cases and deaths to be higher in large cities; however, these growth rates tend to decrease in large cities and to increase in small ones over time.


Prenatal exposure to 900 MHz, cell-phone electromagnetic fields had no effect on operant-behavior performances of adult rats.
To clarify potential health risks of radio-frequency electromagnetic fields (EMFs) used in cellular telephone technology to the developing brain, Wistar rats were continuously exposed during pregnancy to a low-level (0.1 mW/cm(2)) 900 MHz, 217 Hz pulse modulated EMF that approximated the highest legal exposure of normal populations to the radiation of base antennas of the GSM digital cell-phone technology. Whole body average specific absorption rate (SAR) values for the freely roaming, pregnant animals were measured in models; they ranged between 17.5 and 75 mW/kg. The offspring of exposed and of sham-exposed dams were coded and tested later as adults in a battery of ten simultaneously operated test chambers (Skinner boxes) during night time. Eight groups of ten coded animals in each group were tested for learning deficits in a sequence of nine, computer-controlled, 15 h sessions of the food-reinforced contingency Differential Reinforcement of Rate with increasing performance requirements. Two different sets of events were recorded: The food-reinforced lever-pressing activity of the animals and the inter-response intervals (IRIs) between consecutive lever presses. IRI-occurence patterns discriminated consistently between "learners" and "non-learners". Analyses of performance scores and of IRI-patterns both showed that exposure in-utero to the GSM field did not induce any measurable cognitive deficits.


Cholera transmission dynamic models for public health practitioners.
Great progress has been made in mathematical models of cholera transmission dynamics in recent years. However, little impact, if any, has been made by models upon public health decision-making and day-to-day routine of epidemiologists. This paper provides a brief introduction to the basics of ordinary differential equation models of cholera transmission dynamics. We discuss a basic model adapted from Codeço (2001), and how it can be modified to incorporate different hypotheses, including the importance of asymptomatic or inapparent infections, and hyperinfectious V. cholerae and human-to-human transmission. We highlight three important challenges of cholera models: (1) model misspecification and parameter uncertainty, (2) modeling the impact of water, sanitation and hygiene interventions and (3) model structure. We use published models, especially those related to the 2010 Haitian outbreak as examples. We emphasize that the choice of models should be dictated by the research questions in mind. More collaboration is needed between policy-makers, epidemiologists and modelers in public health.


Stability studies needed to define the handling and transport conditions of sensitive pharmaceutical or biotechnological products.
Many pharmaceutical or biotechnological products require transport using temperature-controlled systems to keep their therapeutic properties. There are presently no official guidelines for testing pharmaceutical products in order to define suitable transport specifications. After reviewing the current guidance documents, this paper proposes a methodology for testing pharmaceutical products and defining appropriate transport conditions.


Rapid identification of multidrug-resistant tuberculosis isolates in treatment failure or relapse patients in Bangui, Central African Republic.
Multidrug-resistant (MDR) strains were identified in 40% of 54 strains from patients presenting with tuberculosis (TB) treatment failure or relapse in Bangui, Central African Republic. Results obtained with the MTBDRplus line-probe assay or rpoB sequencing were 86% concordant with rifampicin (RMP) resistant phenotypes, while the amplification refractory mutation system test was 71% concordant. No mutation was found in RMP-susceptible strains. MTBDRplus and sequencing were concordant with the detection of the S315T mutation in katG in 95% of MDR strains. Sequencing of pncA suggested pyrazinamide resistance in 50% of MDR strains. Knowledge of these resistances should help to implement treatment in low-income countries.


How Cancer Genomics Drives Cancer Biology: Does Synthetic Lethality Explain Mutually Exclusive Oncogenic Mutations?
Large-scale analyses of cancer genomes are revealing patterns of mutations that suggest biologically significant ideas about many aspects of cancer, including carcinogenesis, classification, and preventive and therapeutic strategies. Among those patterns is "mutual exclusivity," a phenomenon observed when two or more mutations that are commonly observed in samples of a type of cancer are not found combined in individual tumors. We have been studying a striking example of mutual exclusivity: the absence of coexisting mutations in the KRAS and EGFR proto-oncogenes in human lung adenocarcinomas, despite the high individual frequencies of such mutations in this common type of cancer. Multiple lines of evidence suggest that toxic effects of the joint expression of KRAS and EGFR mutant oncogenes, rather than loss of any selective advantages conferred by a second oncogene that operates through the same signaling pathway, are responsible for the observed mutational pattern. We discuss the potential for understanding the physiological basis of such toxicity, for exploiting it therapeutically, and for extending the studies to other examples of mutual exclusivity.


X13CMS: global tracking of isotopic labels in untargeted metabolomics.
Studies of isotopically labeled compounds have been fundamental to understanding metabolic pathways and fluxes. They have traditionally, however, been used in conjunction with targeted analyses that identify and quantify a limited number of labeled downstream metabolites. Here we describe an alternative workflow that leverages recent advances in untargeted metabolomic technologies to track the fates of isotopically labeled metabolites in a global, unbiased manner. This untargeted approach can be applied to discover novel biochemical pathways and characterize changes in the fates of labeled metabolites as a function of altered biological conditions such as disease. To facilitate the data analysis, we introduce X(13)CMS, an extension of the widely used mass spectrometry-based metabolomic software package XCMS. X(13)CMS uses the XCMS platform to detect metabolite peaks and perform retention-time alignment in liquid chromatography/mass spectrometry (LC/MS) data. With the use of the XCMS output, the program then identifies isotopologue groups that correspond to isotopically labeled compounds. The retrieval of these groups is done without any a priori knowledge besides the following input parameters: (i) the mass difference between the unlabeled and labeled isotopes, (ii) the mass accuracy of the instrument used in the analysis, and (iii) the estimated retention-time reproducibility of the chromatographic method. Despite its name, X(13)CMS can be used to track any isotopic label. Additionally, it detects differential labeling patterns in biological samples collected from parallel control and experimental conditions. We validated the ability of X(13)CMS to accurately retrieve labeled metabolites from complex biological matrices both with targeted LC/MS/MS analysis of a subset of the hits identified by the program and with labeled standards spiked into cell extracts. We demonstrate the full functionality of X(13)CMS with an analysis of cultured rat astrocytes treated with uniformly labeled (U-)(13)C-glucose during lipopolysaccharide (LPS) challenge. Our results show that out of 223 isotopologue groups enriched from U-(13)C-glucose, 95 have statistically significant differential labeling patterns in astrocytes challenged with LPS compared to unchallenged control cells. Only two of these groups overlap with the 32 differentially regulated peaks identified by XCMS, indicating that X(13)CMS uncovers different and complementary information from untargeted metabolomic studies. Like XCMS, X(13)CMS is implemented in R. It is available from our laboratory website at http://pattilab.wustl.edu/x13cms.php .


The distally pedicled peroneus brevis muscle flap: a new flap for the lower leg.
Defects of the skin and soft tissue in the region of the lateral malleolus of the ankle and the Achilles tendon, resulting in exposed bone, tendons, or osteosynthetic material, cannot be covered with free skin transplants. Local or free flaps must be employed. The authors present the construction of a peroneus brevis muscle flap with a distal pedicle as a useful alternative. Between 1993 and 1999, distal pedicled peroneus brevis muscle flaps were used in 19 patients with various types of defects. During construction of the flap, both the long peroneal muscle and the peroneal artery remained intact. In the region of the distal third of the fibula, consistently arranged branches run from the artery into the muscle, and these form the distal pedicle. The proximal portion of the muscle can be transposed distally and easily extends to the tip of the fibula and the attachment of the Achilles tendon to the calcaneus. Primary healing occurred in 16 patients undergoing flap construction. Donor-site morbidity was mostly limited to the donor-site scar. The distally pedicled peroneus brevis muscle flap is a reliable means for covering defects in the lower leg. This form of muscle flap has not yet been described in the known literature. In the authors' opinion, this flap constitutes a logical and valuable extension of local flap procedures for plastic surgery in the distal leg region.


Vitamin K intake and hip fractures in women: a prospective study.
Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K. We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women. We conducted a prospective analysis within the Nurses' Health Study cohort. Diet was assessed in 72327 women aged 38-63 y with a food-frequency questionnaire in 1984 (baseline). During the subsequent 10 y of follow-up, 270 hip fractures resulting from low or moderate trauma were reported. Women in quintiles 2-5 of vitamin K intake had a significantly lower age-adjusted relative risk (RR: 0.70; 95% CI: 0.53, 0.93) of hip fracture than women in the lowest quintile (< 109 microg/d). Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption (RR: 0.55; 95% CI: 0.40, 0.78) for one or more servings per day compared with one or fewer servings per week), the food that contributed the most to dietary vitamin K intakes. Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation.


Quality and costs of supported living residences and group homes in the United Kingdom.
Information was collected on 63 adults in supported living residences, 55 adults in small group homes, and 152 adults in large group homes. Results indicated that (a) there were no statistically significant differences in service costs once these had been adjusted to take account of participant characteristics; (b) compared with participants living in small group homes, those in supported living residences had greater choice, participated in more community-based activities, experienced fewer scheduled activities, were more likely to have had their home vandalized, and were considered at greater risk of exploitation; (c) compared with participants living in large group homes, those in small group homes had larger social networks, more people in their social networks who were not staff, not family, and did not have mental retardation. These residents were considered at less risk of abuse.


A novel polymorphism in a forkhead box A1 (FOXA1) binding site of the human UDP glucuronosyltransferase 2B17 gene modulates promoter activity and is associated with altered levels of circulating androstane-3α,17β-diol glucuronide.
UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyzes the addition of glucuronic acid to testosterone and dihydrotestosterone and their metabolites androsterone and androstane-3α,17β-diol. Hence, changes in UGT2B17 gene expression may affect the capacity of the prostate to inactivate and eliminate male sex hormones. In this work, we identify a prevalent polymorphism, -155G/A, in the proximal promoter of the UGT2B17 gene. This polymorphism modulates UGT2B17 promoter activity, because luciferase-gene reporter constructs containing the -155A allele were 13-fold more active than those containing the -155G allele in prostate cancer LNCaP cells. The -155G/A polymorphism is contained within a putative binding site for the transcription factor Forkhead Box A1 (FOXA1). Using gene reporter, electromobility shift, and chromatin immunoprecipitation analyses, we show that FOXA1 binds to this site and stimulates the UGT2B17 promoter. Furthermore, down-regulation of FOXA1 in LNCaP cells substantially reduces UGT2B17 mRNA levels. The binding of FOXA1 and subsequent stimulation of the UGT2B17 promoter is greatly reduced in the presence of the -155G allele compared with the -155A allele. Consonant with its capacity to be stimulated by FOXA1, the UGT2B17 -155A allele, compared with the -155G allele, is associated with higher levels of circulating androstane-3α,17β-diol glucuronide. Although the initial phases of prostate cancer are androgen-dependent and UGT2B17 inactivates androgens, there was no association of the UGT2B17 -155G/A polymorphism with prostate cancer risk. In summary, this work identifies FOXA1 as an important regulator of UGT2B17 expression in prostate cancer LNCaP cells and identifies a polymorphism that alters this regulation.


The medial prefrontal cortex: a potential link between self-deception and affect.
The Medial Prefrontal Cortex (MPFC) is crucial for normal social functioning in humans. Because of its involvement in social monitoring, self-awareness, and self-enhancement, the MPFC may be critical to buffering negative affect and establishing a positive self-esteem. For example, we have previously found that disruption of the MPFC leads to more honest responses, which implies that the MPFC may be critically involved in self-deception. We therefore hypothesized that disrupting the MPFC would lead to a decrease in affect. Employing a virtual lesion TMS (Transcranial Magnetic Stimulation) technique, we disrupted the MPFC while participants rated their mood based on two anchor affect terms. During TMS, the participants rated their current emotional mental state. Compared to sham TMS, it was found that mood was reduced immediately following single-pulse MPFC stimulation. The results supported the hypothesis the MPFC mood reduction occurs when the MPFC is disrupted. Because this study replicated the conditions employed in previous self-deception studies, we suggest that the results may indicate that lack of self-enhancement may lead to a decrease in mood. Further studies should examine this possibility.


Cells of the mononuclear phagocyte series differentiate into osteoclastic lacunar bone resorbing cells.
Although the osteoclast shares several features with other cells of the mononuclear phagocyte system (MPS), its precise cellular ontogeny is unknown, and its membership of the MPS is controversial. This study examined whether various cells of the MPS can be induced to differentiate into cells capable of the highly specialized osteoclastic function of lacunar bone resorption. We isolated mouse and rat monocytes, mouse (liver, peritoneal, alveolar, brain) tissue macrophages, and spleen and marrow haemopoietic cells, as well as foreign body macrophages and macrophage polykaryons derived from subcutaneous granulomas formed by implantation of latex beads and coverslips in mice. When these cells were incubated with UMR106 osteoblast-like cells on glass coverslips and human cortical bone slices in the presence of 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] for 7 and 14 days, numerous tartrate-resistant acid phosphatase-positive cells formed in these co-cultures and scanning electron microscopy revealed extensive lacunar resorption of the bone surface. Bone resorption was seen as early as 4 days after monocytes were co-cultured with UMR106 cells. With the exception of bone marrow-derived cells, lacunar resorption was not seen in the absence of UMR106 cells. These findings show that a bone-derived stromal cell element is necessary for differentiation of monocytes and tissue and inflammatory macrophages into osteoclast-like cells capable of extensive lacunar bone resorption, and would argue in favour of osteoclast membership of the MPS.


Drinking in denial: a cross-sectional analysis of national survey data in Ireland to measure drinkers' awareness of their alcohol use.
Ireland has high per capita alcohol consumption and also has high levels of problematic drinking patterns. While it is accepted that patterns of alcohol consumption in Ireland are a cause for concern, it is not clear if Irish people are actually aware of the extent of their hazardous or harmful pattern of drinking. The aim of this study was to determine awareness of drinking pattern in an Irish population using a representative random sample and to identify characteristics associated with self-awareness of hazardous or harmful drinking. We analysed data from Ireland's 2014/2015 Drug Prevalence Survey which recruited a stratified clustered sample of 7005 individuals aged 15 years and over living in private households. Logistic regression analysis was used to determine characteristics associated with self-awareness of hazardous or harmful drinking. Almost one half of drinkers had a hazardous or harmful pattern of drinking; 38% engaged in monthly risky single occasion drinking (RSOD) and 10.5% met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for alcohol dependence. Of the 2420 respondents who had a hazardous or harmful pattern of drinking, 67% were unaware of this and misclassified themselves as being either a light or moderate drinker who did not engage in RSOD. An adjusted logistic regression model identified that hazardous and harmful drinkers were more likely to be aware of their drinking pattern if they had completed third level education (OR=1.80, 95% CI: 1.30 to 2.49) while older drinkers (aged 65 and over) were less likely to be aware of their drinking pattern (OR=0.30, 95% CI: 0.14 to 0.65). Subjects who engaged in risk taking behaviours such as illicit drug use and gambling were also significantly more likely to be aware of their drinking pattern. The results of this study suggest that patterns of alcohol use in Ireland are problematic. Older respondents and those with lower educational attainment are less likely to be aware of their hazardous or harmful drinking pattern. There is also a population of younger, more-educated drinkers who engage in potentially risk-taking behaviours and these subjects are aware of their harmful drinking pattern. Initiatives to reduce overall alcohol consumption and raise awareness around drinking patterns are required.


Misinterpretation of conditional statements in Wason's selection task.
Errors may be made on Wason's selection task because either (a) the rule to be tested is misunderstood, or (b) reasoning from that rule is inaccurate, or both. We report two experiments using the experimental paradigm introduced by Gebauer and Laming in which subjects are given six problems in succession. We use the subset of cards selected by each subject as (a) an indication of how the rule is understood and, when that selection is consistent throughout all six problems (so that we can infer a consistent understanding of the rule), as (b) a basis for evaluating the accuracy of the subject's reasoning according to three independent criteria. Experiment 1 adds an exactly parallel contextual version of the task to permit comparison between performances (by the same subjects) on the two versions. Experiment 2 repeats Exp. 1, but with negatives inserted in the conditional rule. Most subjects make a consistent selection of cards throughout all six problems, but typically appear to misunderstand the rule. This is so in both abstract and contextual tasks and replicates the finding by Gebauer and Laming. Most misunderstandings consisted of either (a) reading the simple conditional rule as a bi-conditional or (b) substituting "top/underneath" for "one side/other side". In Exp. 1 subjects seldom misevaluated the rule they appeared to be testing, but such "errors" of evaluation were common in Exp. 2. Negatives confuse the subjects and should not be used in any conditional application that matters. In Exp. 2 (but not 1) there was a significant correlation between interpretations of the two tasks. We provide an explanation of "matching bias" (it results from the confluence of the two common misunderstandings above) and comment on "mental models" which are, at present, unable to accommodate the variety of results we present here. We also relate our experimental paradigm to the conditional inference task and to truth tables.


Singlet fission in self-assembled PDI nanocrystals.
Upon photoexcitation, self-assembled PDI nanocrystals (S1S0) in the form of rods of 70 nm width and 1 μm length are subject to a symmetry breaking charge separation (SBCS) as the first step in the singlet fission (SF) sequence. Hereby, the correlated pair of triplet excited states 1(T1T1) is formed with a quantum yield of 122%. Decoherence and triplet diffusion within the nanocrystals affords a long-lived, uncorrelated pair of triplet excited states (T1 + T1) with a quantum yield of 24%.


Indocyanine green fluorescence imaging for evaluation of uterine blood flow in cynomolgus macaque.
Uterine blood flow is an important factor in uterine viability, but the number of blood vessels required to maintain viability is uncertain. In this study, indocyanine green (ICG) fluorescence imaging was used to examine uterine hemodynamics and vessels associated with uterine blood flow in cynomolgus macaque. The uterus of a female cynomolgus macaque was cut from the vaginal canal to mimic a situation during trachelectomy or uterine transplantation surgery in which uterine perfusion is maintained only with uterine and ovarian vessels. Intraoperative uterine hemodynamics was observed using ICG fluorescence imaging under conditions in which various nutrient vessels were selected by clamping of blood vessels. A time-intensity curve was plotted using imaging analysis software to measure the T(max) of uterine perfusion for selected blood vessel patterns. Open surgery was performed with the uterus receiving nutritional support only from uterine vessels on one side. The size of the uterus after surgery was monitored using transabdominal ultrasonography. The resulting time-intensity curves displayed the average intensity in the regions of the uterine corpus and uterine cervix, and in the entire uterus. Analyses of the uterine hemodynamics in the cynomolgus macaque showed that uterine vessels were significantly related to uterine perfusion (P=0.008), whereas ovarian vessels did not have a significant relationship (P=0.588). When uterine vessels were clamped, ovarian vessels prolonged the time needed to reach perfusion maximum. Postoperative transabdominal ultrasonography showed that the size of the uterus was not changed 2 months after surgery, with recovery of periodic menstruation. The cynomolgus macaque has got pregnant with favorable fetus well-being. Uterine vessels may be responsible for uterine blood flow, and even one uterine vessel may be sufficient to maintain uterine viability in cynomolgus macaque. Our results show that ICG fluorescence imaging is useful for evaluation of uterine blood flow since this method allows real-time observation of uterine hemodynamics.